Abstract
Objective
Anamorelin, a novel selective ghrelin receptor agonist, was approved in Japan for the treatment of cachexia in pancreatic cancer (PC), albeit with limited evidence. This study evaluated the efficacy and safety of anamorelin in PC and examined the impact of the extent of weight loss on the efficacy of anamorelin.
Methods
We retrospectively investigated consecutive PC patients with cachexia who received anamorelin at our institution between June 2021 and January 2022. Patients were divided into two groups: moderate-weight-loss group (5-10%) and severe-weight-loss group (>10%). The primary outcome was changes in body weight. The secondary outcomes were changes in appetite and laboratory measures as well as treatment-related severe adverse events.
Results
A total of 24 patients were included (moderate/severe weight loss: 8/16). The moderate-weight-loss group showed significantly more weight gain than the severe-weight-loss group. Improvements in appetite were consistently observed in each weight-loss group. Changes in laboratory markers were not significantly different between groups. Hyperglycemia (four patients) was the most common cause of severe adverse events, followed by abdominal distension, nausea, elevated liver function tests, and bulimia.
Conclusion
The efficacy of anamorelin was associated with the extent of weight loss. Although anamorelin improved appetite in each weight-loss group, it increased body weight only in the moderate-weight-loss group. Anamorelin was well-tolerated among advanced PC patients, although caution must be practiced when it is used in patients with concomitant diabetes mellitus.
Keywords: anamorelin, anorexia, body weight, cachexia, pancreatic cancer
Introduction
Cancer cachexia is a multifactorial syndrome characterized by progressive weight loss with concomitant loss of muscle and/or fat mass, which leads to functional impairment and reduced physical performance (1). Cancer cachexia has been associated with increased chemotherapy toxicity, a reduced quality of life (QoL), and a poor prognosis in several malignancies, including pancreatic cancer (PC) (2-5).
Establishing effective treatment strategies for cancer cachexia is important for the management of advanced PC, as cancer cachexia is highly prevalent in this population. Nutritional support and exercise have been proposed as promising therapies for cancer cachexia, albeit with limited efficacy (6,7). Administration of pharmacological therapies, including corticosteroids and progestins, is recommended in the American Society of Clinical Oncology guidelines for cancer cachexia (8). However, corticosteroids are recommended only for a short duration due to their side effects, while progestins have been shown to be less effective and have a high incidence of serious adverse effects, including thromboembolic events (9).
Anamorelin, a novel orally-active selective agonist of ghrelin receptor, was shown to be associated with increased lean body mass and body weight and an improved appetite in non-small-cell lung cancer patients with cachexia (10-12). It was subsequently shown to be effective in gastrointestinal cancers, including PC (13), and was approved in Japan in January 2021 for cachexia due to non-small-cell lung cancer, gastric cancer, PC, and colorectal cancer. Recently, the efficacy of anamorelin was also demonstrated in these four types of cancer patients with cachexia and a low body mass index (14). However, data are limited regarding the efficacy and safety of anamorelin in advanced PC due to the limited number of patients included in the previous two studies on the topic [only five patients (13) and six patients (14) in two respective studies]. Furthermore, whether or not the extent of weight loss before administration affects the efficacy of anamorelin has not been elucidated. The present retrospective study evaluated the efficacy and safety of anamorelin in advanced PC patients with cachexia and examined the impact of the extent of weight loss on the efficacy of anamorelin.
Materials and Methods
Patients
Consecutive patients with unresectable advanced PC who met the criteria of cachexia and received anamorelin at our institution between June 2021 and January 2022 were identified from our prospectively obtained database. Cachexia was defined as follows: 1) involuntary weight loss ≥5% within the last 6 months, 2) anorexia, and 3) satisfying ≥2 of the following criteria: i) fatigue, ii) generalized muscle weakness, or iii) ≥1 of C-reactive protein >0.5 mg/dL, hemoglobin <12 g/dL, or albumin <3.2 g/dL. Anorexia, fatigue, and generalized muscle weakness were defined as grade ≥1 symptoms according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0.
Patients were divided into two groups based on the extent of weight loss during the 6 months immediately before anamorelin administration: the moderate-weight-loss group (5-10%) and the severe-weight-loss group (>10%). Patients received 100 mg of anamorelin once daily as long as it was considered effective for the patients, unless it was terminated due to adverse events or clinical deterioration.
This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of our institution (Institutional Review Board number: 2022-GB-041). Written informed consent was waved by the ethics committee due to the retrospective nature of this study.
Assessments and outcomes
The primary outcome of this study was the mean change in body weight from baseline to the evaluable time points (at weeks 4, 8, 12, 16, 20, and 24). Data on body weight were unavailable in two patients and one patient at weeks 4 and 8, respectively. The secondary outcomes of this study included changes in appetite and the mean change in laboratory markers (C-reactive protein, hemoglobin, and albumin) from baseline to the evaluable time points (at weeks 4, 8, 12, 16, 20, and 24). Appetite was assessed by a QoL questionnaire for patients with cancer who were treated with anticancer drugs (QoL-ACD) (appetite-related question 8, “Did you have a good appetite?”) (15) and was scored on a five-point Likert scale (1, not at all; 2, slightly; 3, somewhat; 4, reasonably good; and 5, very much). Treatment-related severe adverse events and reasons for discontinuing anamorelin were also evaluated. The overall survival was defined as the time from the first anamorelin dose until death from any cause or the last follow-up. Follow-up data were confirmed until May 31, 2022.
Statistical analyses
Continuous variables are presented as the means and standard deviation or standard error and were compared using Student's t-test. Categorical variables are described as absolute numbers and proportions and were analyzed using the χ2 test or Fisher's exact test, as appropriate. The overall survival was evaluated using the Kaplan-Meier method, and the Kaplan-Meier curves were compared by the log-rank test. Statistical tests were two-sided, and a p value <0.05 was considered statistically significant. Statistical analyses were carried out using the EZR software version 1.40 (16).
Results
Patient characteristics
A total of 24 consecutive advanced PC patients with cachexia who received anamorelin at our institution were included in this study (Fig. 1). Eight patients were categorized into the moderate-weight-loss group (5-10%), and the remaining 16 patients were categorized into the severe-weight-loss group (>10%). Baseline characteristics of the patients are shown in Table. The means and standard deviations of age, weight, and body mass index for the entire cohort were 67.4±8.9 years old, 46.72±7.68 kg, and 18.92±2.35 kg/m2, respectively. One-third of the patients were men, and more than half had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1. Five patients had moderate or severe ascites, 11 had diabetes mellitus (DM), and 10 were receiving pancreatic enzyme replacement therapy (PERT). A total of 83% had received 1 or 2 anticancer treatments in the past, and 79% were receiving concomitant chemotherapy. These baseline characteristics were not significantly different between the two groups, except for a tendency toward an older age in the moderate-weight-loss group (72.3 vs. 64.9 years old, p=0.055).
Figure 1.
Patient flowchart.
Table.
Patient Characteristics.
| Entire cohort n=24 |
Moderate body weight loss n=8 |
Severe body weight loss n=16 |
p value | ||
|---|---|---|---|---|---|
| Age, years | 67.4±8.9 | 72.3±7.6 | 64.9±8.6 | 0.055 | |
| Sex | Male | 8 (33%) | 3 (38%) | 5 (31%) | >0.999 |
| Weight, kg | 46.72±7.68 | 48.66±6.13 | 45.74±8.36 | 0.392 | |
| Body mass index, kg/m2 | 18.92±2.35 | 19.21±2.50 | 18.78±2.34 | 0.677 | |
| Weight loss before anamorelin | |||||
| 5-10% | 8 (33%) | ||||
| >10% | 16 (67%) | ||||
| ECOG PS | 0.543 | ||||
| 0 | 8 (33%) | 2 (25%) | 6 (38%) | ||
| 1 | 14 (58%) | 6 (75%) | 8 (50%) | ||
| 2 | 2 (8%) | 0 | 2 (13%) | ||
| Disease status | 0.260 | ||||
| Locally-advanced | 3 (13%) | 2 (25%) | 1 (6%) | ||
| Metastatic | 17 (71%) | 4 (50%) | 13 (81%) | ||
| Recurrence | 4 (17%) | 2 (25%) | 2 (13%) | ||
| Ascites | Moderate or severe | 5 (21%) | 2 (25%) | 3 (19%) | >0.999 |
| Diabetes mellitus | Yes | 11 (46%) | 5 (63%) | 6 (38%) | 0.390 |
| PERT | Yes | 10 (42%) | 3 (38%) | 7 (44%) | >0.999 |
| Concomitant cancer therapy | Yes | 19 (79%) | 8 (100%) | 11 (69%) | 0.130 |
| Combination chemotherapy | Yes | 10 (42%) | 4 (50%) | 6 (38%) | 0.673 |
| modified FOLFIRINOX | 2 | 0 | 2 | ||
| S-IROX | 1 | 0 | 1 | ||
| Nal-IRI plus 5-FU/LV | 5 | 2 | 3 | ||
| Gemcitabine plus nab-paclitaxel | 2 | 2 | 0 | ||
| Monotherapy | Yes | 9 (38%) | 4 (50%) | 5 (31%) | 0.412 |
| Gemcitabine | 6 | 2 | 4 | ||
| S-1 | 3 | 2 | 1 | ||
| Number of prior chemotherapy regimens | >0.999 | ||||
| 0 | 1 (4%) | 0 | 1 (6%) | ||
| 1 | 8 (33%) | 3 (38%) | 5 (31%) | ||
| 2 | 12 (50%) | 4 (50%) | 8 (50%) | ||
| ≥ 3 | 3 (13%) | 1 (13%) | 2 (13%) |
Continuous variables are expressed as mean±standard deviation and categorical variables are expressed as absolute numbers (proportions).
ECOG: Eastern Cooperative Oncology Group, PS: performance status, PERT: pancreatic enzyme replacement therapy, S-IROX: S-1 plus irinotecan and oxaliplatin combination therapy, Nal-IRI: nanoliposomal irinotecan, 5-FU/LV: fluorouracil/folinic acid
Primary outcome
The mean percent changes in body weight from baseline to week 24 are illustrated in Fig. 2. In the entire cohort, the body weight increased at week 4 (mean and standard error, 2.56 ±0.84%) but was not sustained thereafter. When stratified by the extent of weight loss (moderate vs. severe weight loss), the moderate-weight-loss group showed a significantly larger weight gain than the severe-weight-loss group (means and standard errors were 4.65±1.09% vs. 1.31±1.01%, p=0.049, at week 4; 3.35±1.30% vs. -2.16±1.34%, p=0.017, at week 8; 6.91±3.69% vs. -5.74±1.62%, p=0.007, at week 12; and 3.10±2.37% vs. -5.21±0.52%, p=0.027, at week 16, respectively). Similar results were also observed for specific mean changes in body weight from baseline to week 24 (Supplementary material 1).
Figure 2.
Percent changes in body weight from baseline to week 24. (A) Entire cohort. (B) Stratified by the extent of weight loss.
Secondary outcomes
The mean changes in the QoL-ACD score for item 8 (“Did you have a good appetite?”) from baseline to week 24 are shown in Fig. 3. Improvements in appetite were consistently observed both in the entire cohort and in each weight-loss group through week 24. There was no significant difference in the mean score change between the two groups. Mean changes in laboratory markers are shown in Supplementary material 2. No significant difference was observed between the two groups in any of the evaluated markers.
Figure 3.
Changes in the score for item 8 (“Did you have a good appetite?”) of the quality-of-life questionnaire from baseline to week 24 for patients who were treated with anticancer drugs. (A) Entire cohort. (B) Stratified by the extent of weight loss.
Safety
During the study period, 17 patients (71%) died of cancer, without any anamorelin-related mortality. The median overall survival was not significantly different between the 2 groups (205 vs. 133 days, p=0.388) (Fig. 4). Anamorelin was discontinued in 22 patients (7 and 15 patients in the moderate- and severe-weight-loss groups, respectively). The mean treatment duration of anamorelin was longer in the moderate-weight-loss group than in the severe-weight-loss group (118 vs. 63 days, p=0.102), although the difference was not significant. Reasons for treatment discontinuation were clinical deterioration in 12 patients (3 and 9 patients in the moderate- and severe-weight-loss groups, respectively), inefficacy in 2 patients (both in the severe-weight-loss group), and treatment-related severe adverse events in 8 patients (4 patients each in the moderate- and severe-weight-loss groups). Hyperglycemia (four patients; three and one in the moderate- and severe-weight-loss groups, respectively) was the most common severe adverse event, followed by abdominal distension (one patient in the moderate-weight-loss group), nausea (one patient in the severe-weight-loss group), elevated liver function tests (one patient in the severe-weight-loss group), and bulimia (one patient in the severe-weight-loss group). All four patients who developed hyperglycemia had concomitant DM.
Figure 4.
Kaplan-Meier curves of the overall survival of pancreatic cancer patients stratified by the extent of weight loss.
Discussion
The current study evaluated the efficacy and safety of anamorelin in advanced PC patients with cachexia, with a focus on the extent of weight loss before administration. This study demonstrated several important findings. First, the efficacy of anamorelin was associated with the extent of weight loss. Although improvements in appetite were consistently observed in the entire cohort, regardless of the extent of weight loss, improvements in body weight were only observed in the moderate-weight-loss group. Both the median overall survival and treatment duration of anamorelin were longer in the moderate-weight-loss group than in the severe-weight-loss group, although the difference was not significant. Second, hyperglycemia was the most common adverse events which led to treatment discontinuation in advanced PC patients with DM. To our knowledge, this is the largest study to evaluate the efficacy of anamorelin in advanced PC and the first to demonstrate the impact of previous weight loss on the efficacy of anamorelin.
Cancer cachexia is subdivided into three stages: pre-cachexia, cachexia, and refractory cachexia (1). The pre-cachexia and cachexia stages are suspected to be reversible with combination therapy with nutritional support, exercise, and pharmacological therapy, while the refractory cachexia stage is considered to be irreversible, highlighting the need for early intervention. Therefore, the efficacy of anamorelin may be affected by the severity of cachexia, which may be reflected in the degree of weight loss.
Data regarding the efficacy and safety of anamorelin in advanced PC patients with cachexia are lacking. In the present study, the administration of anamorelin led to improvements in both appetite and body weight in the moderate-weight-loss group, which was consistent with the results of previous studies (10,11,13,14,17). However, improvements in appetite by anamorelin did not lead to weight gain in the severe-weight-loss group. One explanation for this may be that patients with advanced PC tend to lose more weight than those with other types of cancer (18). Compared with two previous studies (11,13) reporting the extent of weight loss at baseline, our study cohort had a higher rate of patients with a weight loss >10% (42.2% and 46.9% in the previous studies vs. 67% in the present study). As the extent of weight loss can be related to the severity of cachexia to some extent, our study may suggest that use of anamorelin does not lead to weight gain in PC patients with advanced stage of cachexia. If this is true, anamorelin should be administered in the early stages of cachexia in order to achieve favorable outcomes.
The frequency of hyperglycemia that led to treatment discontinuation was high (17%) relative to previous studies. This could be explained by the higher rate of concomitant DM in this study, as patients with advanced PC have a higher prevalence of DM than those with other types of cancer (19). Furthermore, this real-world study also included patients with uncontrolled DM, who were excluded in previous studies (11-13). Other types of previously reported common adverse events, including cardiac conduction disorders, were not frequently observed in the present study. Of note, one patient in our study discontinued anamorelin due to bulimia resulting from an insuppressible appetite. Anamorelin was generally well-tolerated among advanced PC patients with cachexia, although caution must be taken when administering anamorelin in patients with concomitant DM. Close monitoring and management by a diabetes specialist may be needed.
Notably, several questions remain unanswered. First, whether or not anamorelin is effective in advanced PC patients with an ECOG PS of ≥ 2 is unclear, as previous studies excluded such patients. In the present study, two patients had an ECOG PS of 2 (both were in the severe-weight-loss group). The treatment duration of anamorelin (3 and 26 days) and overall survival (30 and 59 days) were very short in these patients, suggesting that advanced PC with a poor ECOG PS may not be a good indication for anamorelin. Second, whether or not anamorelin can improve the prognosis of patients with cachexia has not been well-studied. In the present study, although the baseline characteristics were similar between the weight-loss groups, the overall survival was longer in the moderate-weight-loss group than in the severe-weight-loss group, although there was no significant difference. As PERT was reported to have a survival benefit in advanced PC in a systematic review (20), we speculate that anamorelin may also improve the prognosis of patients with cachexia, considering its positive effects on body weight and appetite. Third, the impact of multimodal treatment including nutritional support, exercise, and pharmacological therapy needs to be examined further (21-23). Finally, the underlying mechanism behind cancer cachexia has not been fully elucidated. Novel biomarkers may be needed for the early diagnosis of cachexia and identification of specific subgroups likely to benefit most from treatment.
However, several limitations associated with the present study warrant mention. First, this was a retrospective study with a limited sample size from a single institution. However, this is the largest study to date evaluating the efficacy of anamorelin in advanced PC. Second, a control group was not set in this study, as anamorelin had already been approved in Japan for the treatment of cancer cachexia. Third, we did not examine changes in the dietary intake, including specific calorie intake. However, it is difficult to obtain such objective data in daily clinical practice unless the patient is hospitalized. Finally, the lean body mass and motor function were not evaluated (e.g., through handgrip strength and the 6-minute walk test). However, these tests are not routinely performed in daily clinical practice.
In conclusion, the efficacy of anamorelin is associated with the extent of weight loss before administration. Although anamorelin improved both appetite and body weight in the moderate-weight-loss group, it improved appetite but not body weight in the severe-weight-loss group. Anamorelin was well-tolerated among advanced PC patients with cachexia, although caution must be taken when administering anamorelin in patients with concomitant DM.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Changes in body weight from baseline to week 24. (A) Entire cohort. (B) Stratified by the extent of weight loss.
Changes in body weight from baseline to week 24. (A) Entire cohort. (B) Stratified by the extent of weight loss.
Changes in laboratory measures from baseline to week 24, stratified by the extent of weight loss. (A) Albumin. (B) Hemoglobin. (C) C-reactive protein.
Changes in laboratory measures from baseline to week 24, stratified by the extent of weight loss. (A) Albumin. (B) Hemoglobin. (C) C-reactive protein.
Changes in laboratory measures from baseline to week 24, stratified by the extent of weight loss. (A) Albumin. (B) Hemoglobin. (C) C-reactive protein.
Acknowledgement
The authors thank all of the patients for their contribution to this study.
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Associated Data
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Supplementary Materials
Changes in body weight from baseline to week 24. (A) Entire cohort. (B) Stratified by the extent of weight loss.
Changes in body weight from baseline to week 24. (A) Entire cohort. (B) Stratified by the extent of weight loss.
Changes in laboratory measures from baseline to week 24, stratified by the extent of weight loss. (A) Albumin. (B) Hemoglobin. (C) C-reactive protein.
Changes in laboratory measures from baseline to week 24, stratified by the extent of weight loss. (A) Albumin. (B) Hemoglobin. (C) C-reactive protein.
Changes in laboratory measures from baseline to week 24, stratified by the extent of weight loss. (A) Albumin. (B) Hemoglobin. (C) C-reactive protein.